NM_000059.4(BRCA2):c.116C>T (p.Ala39Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000130510.21

Allele description [Variation Report for NM_000059.4(BRCA2):c.116C>T (p.Ala39Val)]

NM_000059.4(BRCA2):c.116C>T (p.Ala39Val)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.116C>T (p.Ala39Val)

Other names:

p.A39V:GCT>GTT

HGVS:

NC_000013.11:g.32319125C>T
NG_012772.3:g.8646C>T
NG_017006.2:g.1239G>A
NM_000059.4:c.116C>TMANE SELECT
NP_000050.2:p.Ala39Val
NP_000050.3:p.Ala39Val
LRG_293t1:c.116C>T
LRG_293:g.8646C>T
LRG_293p1:p.Ala39Val
NC_000013.10:g.32893262C>T
NM_000059.3:c.116C>T
p.A39V

Nucleotide change:

344C>T

Protein change:

A39V

Links:

dbSNP: rs398122724

NCBI 1000 Genomes Browser:

rs398122724

Molecular consequence:

NM_000059.4:c.116C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185379	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29884841, 31131967, 31811167 Citation Link,
SCV000911388	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28608266, 33471991, 35979650, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185379

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 9, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000911388

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 20, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models.

Hart SN, Hoskin T, Shimelis H, Moore RM, Feng B, Thomas A, Lindor NM, Polley EC, Goldgar DE, Iversen E, Monteiro ANA, Suman VJ, Couch FJ.

Genet Med. 2019 Jan;21(1):71-80. doi: 10.1038/s41436-018-0018-4. Epub 2018 Jun 8.

PubMed [citation]

PMID:: 29884841
PMCID:: PMC6287763

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, et al.

Hum Mutat. 2019 Sep;40(9):1557-1578. doi: 10.1002/humu.23818.

PubMed [citation]

PMID:: 31131967
PMCID:: PMC6772163

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000185379.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.A39V variant (also known as c.116C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 116. The alanine at codon 39 is replaced by valine, an amino acid with similar properties. This alteration has been reported in one Norwegian family with multiple early-onset cancers (Dominguez-Valentin M et al. Fam. Cancer. 2018 Jan;17:141-153). This alteration was also cited as likely benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat. 2019 09;40(9):1557-1578). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000911388.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces alanine with valine at codon 39 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). RNA studies using a minigene assay and patient-derived RNA have shown that this variant does not impact splicing (PMID: 28608266, 35979650). A functional study has reported that this variant does not impact BRCA2 function in the complementation of Brca2-deficient mouse embryonic stem cells and in a homology-directed DNA repair assay (PMID: 35979650). This variant has been reported in an individual affected with bilateral breast cancer, this individual also carried a pathogenic variant in the CHEK2 gene that could explain the observed phenotype (PMID: 28608266). In a large breast cancer case-control study conducted by the BRIDGES consortium this variant was reported in 5/60466 cases and 3/53461 unaffected controls, showing inconclusive association with disease (OR=1.474, 95%CI 0.352 to 6.167, p-value=0.731) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007683). This variant has been identified in 1/251240 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 29, 2024

ClinVar

Relating variation to medicine